Photoreceptor loss associated with retinal degenerative disorders such as retinitis pigmentosa, macular degeneration, and Usher's syndrome is a leading cause of blindness in humans. Photocoagulation and intravitreal VEGF aptamer, the only treatment options for retinal degenerative disorders, are of limited value in majority of the retinal degeneration patients, and do not specifically target the rescue of photoreceptors. Thus, there is a pressing need for a pharmacological approach capable of reducing photoreceptor degeneration, which is the focus of this proposal. A logical approach to treat retinal degenerative disorders would be to develop therapeutic agents capable of promoting photoreceptor survival. During the last decade, lens epithelium-derived growth factor (LEDGF) was identified, characterized, and demonstrated to be a survival factor for photoreceptor cells, retinal pigment epithelial cells, and other cell types against multiple stresses. Most importantly, intravitreal injections of LEDGF have rescued photoreceptor cells in light-damaged Sprague-Dawley rats and RCS rats, indicating the therapeutic potential of LEDGF. Since the therapy for retinal degenerative disorders will likely be chronic and because repeated intravitreal injections can cause complications such as cataracts, endophthalmitis, and retinal detachment, we propose to develop a transscleral approach for the sustained retinal delivery of LEDGF and obtain evidence for the effectiveness of this approach. The objective of this study is to provide proof of the principle for the hypothesis that subconjunctivally administered LEDGF in the form of microparticles reaches the retina in a sustained manner and reduces photoreceptor loss in S334ter-4 and RCS-p+ rat models for sustained retinal degeneration. This hypothesis will be tested using the following two specific aims. 1) To determine whether nanoporous LEDGF-PLGA microparticles sustain LEDGF release. 2) To determine whether nanoporous LEDGF-PLGA microparticles sustain retinal LEDGF delivery and reduce photoreceptor loss in rats following subconjunctival administration. This study will utilize supercritical fluid technology for controlling particle porosity, LEDGF release, and residual solvent content in microparticles and immunochemical methods for assessing retinal LEDGF delivery. In addition, the effect of this mode of LEDGF delivery on retinal ERGs, number of surviving photoreceptor cells, and retinal histology will be determined in the rat models for retinal degeneration. Photoreceptor loss associated with retinal degenerative disorders such as retinitis pigmentosa, macular degeneration, and Usher's syndrome is a leading cause of blindness in humans. Photocoagulation and intravitreal VEGF aptamer, the only treatment options for retinal degenerative disorders, are of limited value in majority of the retinal degeneration patients, and do not specifically target the rescue of photoreceptors. Thus, there is a pressing need for a pharmacological approach capable of reducing photoreceptor degeneration, which is the focus of this proposal. [unreadable] [unreadable] [unreadable]